The pharmacokinetics of liposomal formulations can be improved if the vesicles can be maintained in circulation. An important mechanism for clearance of liposomal formulations is thought to involve the adsorption of proteins onto the liposome surface which mediates subsequent clearance by the cells of the reticuloendothelial system (RES). This clearance may be reduced by the attachment of hydrophilic polymers, such as polyethyleneglycol (PEG), to the liposome surface. These polymers may act in one or both of two ways: (i) they may inhibit or stop protein adsorption on to the liposome's surface, or (ii) they may act as a "steric barrier" to inhibit interactions between the cells involved in clearance and any proteins that might be bound to the liposome surface. The steric barrier effect may also be used to inhibit aggregation in some systems.
PEG-lipid conjugates are used in some commercial liposome formulations to create a steric barrier at the liposome surfaces. PEG is attractive because it is cheap, readily available, non immunogenic and is soluble in all but the most apolar of solvents (see, Torchlin, et al., Biochim. Biophys. Acta., 1195:11-20 (1994); Parr, et al., Biochim. Biophys. Acta., 1195:11-20 (1994); and Woodle, et al., Bioconjugate Chem., 5:493 (1994)). The latter properties allow easy conjugation to a wide range of substrates.
U.S. Pat. No. 5,013,556 and European Patent Applications Nos. 0572 049 A2 and 0 354 855 describe liposomes bearing PEG moieties covalently linked to the external surface. As described therein, the PEG moieties are linked to amino groups in the head group of at least one phospholipid species forming the liposomes.
U.S. Pat. No. 4,426,330 describes phospholipids wherein the polar head group has been modified by covalent attachment of a PEG moiety. European Patent Application No. 0 220 797 A2 describes a process for the preparation of liposomes.
One major drawback of the use of polyethylene glycol is that it exists as a distribution of oligomers with different molecular weights. Further, batch to batch variation can occur. Thus, the properties of the PEG-bound liposomes will vary. What is needed in the art is a specific molecular weight material of defined length to allow selective properties to be imparted to liposomes or other drug delivery systems. The present invention fulfills this and other needs.